Increasingly, biodegradable polymers are being used to replace plastic materials formed from petroleum-based products. Biodegradable polymers are used in many different types of products including packaging, building materials, agriculture and medicine. The biodegradable polymers may be synthetic or natural. Additionally, improvements in the mechanical properties of biodegradable polymers are desired to meet more stringent performance requirements, such as stiffness, dimensional stability and modulus.
One potential use for biodegradable polymers having improved properties is for implantable constructs, for example in structural tissue engineering. Presently, autogenous bone (autograft) remains a gold standard in numerous surgeries requiring bone grafting to achieve arthrodesis and fracture union. The inherent osteoinductivity of autograft coupled with its biomechanical strength make it a clear choice for the reconstruction or replacement of load bearing structures in the body. Despite the success of surgical procedures utilizing autograft, complication rates as high as 30% have been associated with the harvest procedure. (Malloy K. M. and Hilibrand, A. S., Clinical Orthopaedics and Related Research, 394:27-38, 2002; Samartzis D, Shen F H, Matthews D K, Yoon St, Goldberg E F, An H S, Spine J., 3(6): 451-459. 2003; Wigfield C. C., Nelson R. J., Spine, 26:6:687-694, 2001.) These complications include harvest site necrosis and significant post-operative pain and fracture at the harvest site. Arribas-Garcia I, Alcala-Galiano A, Garcia A F, Moreno J J., Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 107(6): e12-14, 2009; Hu R. W. and Bohlman H. H., Clinical Orthopaedics and Related Research, 309:208-213, 1994.)
Allogenic bone (allograft) has been used in place of autograft. (Samartzis et al., Id., Wigfield et al., Id.) Modern donor screening and sterilization methods have significantly reduced the rates of disease transmission, which until fairly recently was a significant risk in allogenic bone graft procedures. The mechanical properties as well as the osteoinductive capacity of allograft have been shown to be dependent on the type of sterilization employed (Malloy et al., Id; Chau A M, Mobbs R J., Eur Spine J., 18(4): 449-464, 2009.) Additionally, allograft bone is in limited supply in some regions, which can limit its applicability in major surgical procedures, such as scoliosis correction. (Chau et al., Id., Moroni A, Larsson S, Hoang Kim A, Gelsomini L, Giannoudis P V, J Orthop Trauma, 23(6): 422-425, 2009.
Given the limitations of autograft and allograft bone, much attention has been given to the development of structural bone graft substitute materials. Ceramic materials, such as the calcium phosphates have been investigated as bone graft substitutes for load bearing applications. (Wigfield et al., Id.) While porous calcium phosphate, such as corraline hydroxyapatite, has high compressive strengths, the brittle nature of the material can lead to progressive collapse of the graft resulting in poor bone healing. (Chau et al., Id.) Porous metallic constructs, such as Trabecular Metal™ (Tantalum, Zimmer Inc., Warsaw Ind.) and Tritanium™ (commercially pure Titanium, Stryker Orthopaedics, Mawah N.J.) have also been introduced as structural bone graft substitutes. The load bearing capacities of porous metal constructs are well documented in both static and dynamic conditions. Unfortunately, long-term implantation of non-resorbing implants is associated with an omni-present risk of infection. Further, the presence of a porous metallic construct may severely limit surgical options if a revision procedure is necessary.
Due to such limitations in the currently available materials, there has been significant interest in developing biodegradable or resorbable polymers for structural bone graft substitute applications. (Chau et al., Id.; Moroni et al., Id.) Numerous methods have been employed to impart a porous structure to resorbable polymers in the hopes of encouraging bone growth. These methods include thermal/pressure induced phase separation, particulate leaching and gas foaming. (Baker K C, Bellair R J, Manitiu M, Herkowitz H N, Kannan R H, J Mech Behav Biomed Mater., 2(6): 620-626, 2009; Georgiou, G., Mathieu, L., Pioletti, D. P., Bourban P.-E., Manson, J.-A. E., Knowles, J. C., and Nazhat, S. N., J. Biomed Mater Res Part B: Appl Biomater. 80B: 322-331, 2007; Hu Y, et al., J Biomed Mater Res. 59: 563-572, 2001; Mathieu, L. M., Montjovent, M.-O., Bourban, P-E., Pioletti, D. P. and Manson, J.-A. E., J. Biomed Mater Res., 75A:89-97, 2005; Nam Y S, Park T G., J Biomed Mat Res, 47: 8-17, 1999.) Phase separation techniques often involve the use of volatile organic solvents which can be detrimental to cell growth. (Nam et al., Id.; Teng X, et al., J Biomed Mater Res B: Applied Biomaterials, 81B: 185-193, 2007.) Particulate leaching must be used in combination with other methods, such as phase separation to yield a construct with connected porosity. Gas foaming techniques, such as supercritical carbon dioxide (scCO2), avoid the use of harmful solvents and may not require additional methods to impart an interconnected porous structure. (Baker et al., Id.; Georgiou et al., Id.; Hu et al., Id.; Gualandi C, White L J, Chen L, Gross R A, Shakesheff K M, Howdle S M, Scandola M, Acta Biomater, 6(1): 130-136, 2010.)
The mechanical properties of porous resorbable constructs synthesized by the aforementioned means are not suitable for load bearing applications as the compressive modulus and compressive strengths are much lower than that of native bone. Failure of the constructs to withstand physiologic loading conditions may result in a reduced rate of healing and in some conditions may necessitate a revision surgical procedure. Researchers have examined reinforcing the polymer constructs with calcium phosphates (hydroxyapatite, β-TCP), phosphate glass and carbon nanotubes. (Georgiou et al., Id.; Mathieu et al., Id.; Kim S S, Ahn K M, Park M S, Lee J H, Choi C Y, Kim B S, J Biomed Mater Res A, 80(1): 206-215, 2007; Khan Y, Yaszemski M J, Mikos A G, Laurencin C T, Bone Joint Surg Am, 9-: 36-42, 2008; Rezwan K, Chen Q Z, Blaker J J, Boccacini A R, Biomaterials, 27(18): 3413-3431, 2006; Wang Y, et al., J Biomed Mater Res A, 86(1): 244-252, 2008.) The addition of these materials to polymer matrices has resulted in modest gains in compressive strength and modulus. Calcium phosphates and phosphate glass particles have a tendency to agglomerate within polymer mixtures, which results in local heterogeneity that is detrimental to mechanical strength. (Georgiou et al., Id.)
Recently, organically modified montmorillonite clays have been investigated as potential reinforcing agents in polymeric matrices. (Horsch, S., Gulari, E. and Kannan, R. J., Polymer, 47:7485-7496, 2006; Manitiu M, Bellair R J, Horsch S, Gulari E, Kannan R M., Macromolecules, 41(21): 8038-8046, 2008, Pavlidou S, Papspyrides C D, Prog Poly Sci, 33: 1119-1198, 2008; Ray S S, Okamoto M, Prog Poly Sci, 23: 1524-1543, 2003; Zeng C, et al., Adv Mater, 15(20): 1743-1747, 2003.) The clays particles are composed of silicate platelets which are approximately 100-5000 nm in length and 1 nm thick. Platelets are held together by van der Waals forces and the equilibrium platelet spacing of 1 nm is generally modified by chemical techniques. One method of increasing platelet spacing is modification of the clay surface with alkylammonium salts. Increasing the spacing of the clay platelets increases the potential for intimate contact between polymer chains and numerous clay platelets, thus reducing polymer chain mobility and improving mechanical properties. (Horsch et al., Id.; Manitiu et al., Id.; Pavilidou et al., Id.; Ray et al., Id.) The processing method used to create clay-polymer nanocomposites also plays a role in the resulting mechanical behavior. Melt processing, high shear mixing and post-processing heat treatments have been employed to enhance polymer chain-clay platelet contact, with moderate property improvements. (Pavilidou et al., Id.; Ray et al., Id.) Researchers have also used scCO2 processing to improve mechanical properties of polymer-clay nanocomposites. (Horsch et al., Id.; Manitiu et al., Id.; Zeng et al., Id.) Diffusion of CO2 within the clay particles and rapid depressurization leads to an increase in platelet spacing, as well as polymer chain contact. (Horsch et al., Id.; Manitiu et al., Id.)
There is therefore a need to develop a biodegradable polymer nanocomposite system and synthesis route which results in porous constructs with a substantially uniform dispersion of reinforcing particles. In addition, there is a need for biodegradable porous nanocomposites suitable for load-bearing applications and for implantation that may be resorbed over time.